Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity

The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expre...

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Bibliographic Details
Published in:Nature communications Vol. 15; no. 1; pp. 633 - 19
Main Authors: Zhang, Xue, Pant, Shishir M., Ritch, Cecily C., Tang, Hsin-Yao, Shao, Hongguang, Dweep, Harsh, Gong, Yao-Yu, Brooks, Rebekah, Brafford, Patricia, Wolpaw, Adam J., Lee, Yool, Weeraratna, Ashani, Sehgal, Amita, Herlyn, Meenhard, Kossenkov, Andrew, Speicher, David, Sorger, Peter K., Santagata, Sandro, Dang, Chi V.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 20.01.2024
Nature Publishing Group
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Subjects:
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45/77
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Animals
ARNTL Transcription Factors - genetics
ARNTL Transcription Factors - metabolism
Biological clocks
BMAL1 protein
Carcinogenesis - genetics
Circadian Clocks - genetics
Circadian rhythm
Circadian Rhythm - genetics
Circadian rhythms
Cytoskeleton
Ectopic expression
Gene expression
Humanities and Social Sciences
Humans
Hypoxia
Immunity
Melanoma
Melanoma - genetics
Mice
multidisciplinary
Myosin
Science
Science (multidisciplinary)
Transcription factors
Tumorigenesis
Tumorigenicity
Tumors
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expression and tumorigenesis, which could be rescued by ectopic expression of HIF1α in YUMM2.1 cells. By contrast, over-expressed wild-type or a transcriptionally inactive mutant Bmal1 non-canonically sequester myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM2.1 cells from a Sox10 high to a Sox9 high immune resistant, mesenchymal cell state that is found in human melanomas. Our work describes a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton. It has been reported that the circadian clock regulator Bmal1 can modulate tumorigenesis. Here the authors show that ectopic expression of Bmal1 promotes an immune resistant mesenchymal melanoma cell state associated with increased AP-1 activity.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-44778-2